EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

Bademosi, Adekunle T.; Decet, Marianna; Kuenen, Sabine; Calatayud, Carles; Swerts, Jef; Gallego, Sandra F; Schoovaerts, Nils; Karamanou, Spyridoula; Louros, Nikolaos; Martin, Ella; Sibarita, Jean‐Baptiste; Vints, Katlijn; Gounko, Natalia V.; Meunier, Frédéric A.; Economou, Anastassios; Versées, Wim; Rousseau, Frédéric; Schymkowitz, Joost; Soukup, Sandra-F; Verstreken, Patrik

doi:10.1016/j.neuron.2023.02.001

Cited by 14 publications

(16 citation statements)

References 118 publications

(194 reference statements)

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“…Our data strongly support that neurons utilize secretory autophagy as a mechanism to communicate and coordinate activity-induced synaptic remodeling. First, consistent with reports that neuronal activity induces autophagy activation ( 41–43 ), we observed elevated GFP-Atg8a signal post-stimulation (Fig. 5F, G).…”

Section: Discussionsupporting

confidence: 92%

“…It will be interesting to delineate mechanisms by which lysozyme signaling regulate synaptic plasticity in the future. Note that while we observed an increase in GFP-Atg8a signal consistent with increased autophagy activation during neuronal activity, we did not detect an increase in the number of mCherry-Atg8a spots (which also labels autolysosomes in addition to autophagosomes) as reported previously for prolonged neuronal stimulation ( 41, 43 ). This difference is likely due to different stimulation conditions, as a 30-minute stimulation was required to elevate mCherry-Atg8a signal ( 41 ).…”

Section: Discussionsupporting

confidence: 87%

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Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling

Chang,

Gao,

Lee

et al. 2023

Preprint

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The ability of neurons to rapidly remodel their synaptic structure and strength in response to neuronal activity is highly conserved across species and crucial for complex brain functions. However, mechanisms required to elicit and coordinate the acute, activity-dependent structural changes across synapses are not well understood. Here, using an RNAi screen inDrosophilaagainst genes affecting nervous system functions in humans, we uncouple cellular processes important for synaptic plasticity from synapse development. We find mutations associated with neurodegenerative and mental health disorders are 2-times more likely to affect activity-induced synaptic remodeling than synapse development. We further demonstrate that neuronal activity stimulates autophagy activation but diminishes degradative autophagy, thereby driving the pathway towards autophagy-based secretion. Presynaptic knockdown of Snap29, Sec22, or Rab8, proteins implicated in the secretory autophagy pathway, is sufficient to abolish activity-induced synaptic remodeling. This study uncovers secretory autophagy as a novel trans-synaptic signaling mechanism modulating structural plasticity.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 87%

Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling

Chang,

Gao,

Lee

et al. 2023

Preprint

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“…Electrical nerve stimulation or treatment with the calcium-channel agonist Nefiracetam leads, within thirty minutes, to the formation of Atg8-positive autophagosomes at Drosophila melanogaster synapses. Our work further points out that mainly extracellular calcium triggers autophagy induction in response to neuronal activity and that this process relies on EndoA [ 1 ] . Previous studies showed that calcium dynamics dictate SH3GL2 interaction with DNM1 (dynamin 1) and voltage-gated calcium channels at the plasma membrane.…”

supporting

confidence: 57%

Endophilin-A/SH3GL2 calcium switch for synaptic autophagy induction is impaired by a Parkinson’s risk variant

Decet

Soukup

2023

Autophagy

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At the synapse, proteins are reused several times during neuronal activity, causing a decline in protein function over time. Although emerging evidence supports a role of autophagy in synaptic function, the precise molecular mechanisms linking neuronal activity, autophagy and synaptic dysfunction are vastly unknown. We show how extracellular calcium influx in the pre-synaptic terminal constitutes the initial stimulus for autophagosome formation in response to neuronal activity. This mechanism likely acts to rapidly support synaptic homeostasis and protein quality control when intense neuronal activity challenges the synaptic proteome. We identified a residue in the flexible region of EndoA (Endophilin A) that dictates calcium-dependent EndoA mobility from the plasma membrane to the cytosol, where this protein interacts with autophagic membranes to promote autophagosome formation. We discovered that a novel Parkinson’s disease-risk mutation in SH3GL2 (SH3 domain containing GRB2 like 2, endophilin A1) disrupts the calcium sensing of SH3GL2, leading to an immobile protein that cannot respond to calcium influx and therefore disrupting autophagy induction at synapses. Our work shows how neuronal activity is connected with autophagy to maintain synaptic homeostasis and survival.

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“…Recent studies in the Drosophila visual system underscore the importance of temporally regulated autophagy during circuit formation 28,29 . We also found that PDZD8 is required for activity-dependent synaptic growth when the requirement for autophagy is likely high as increased synaptic activity has been shown to induce autophagy at the Drosophila NMJ 34 61 . In this context, PDZD8-dependent acceleration of autophagy could serve as a mechanism for translating neural activity into synaptic growth.…”

Section: Discussionmentioning

confidence: 58%

PDZD8 promotes autophagy at ER-Lysosome contact sites to regulate synaptogenesis

Thakur,

O’Connor-Giles

2023

Preprint

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SUMMARYBuilding synaptic connections, which are often far from the soma, requires coordinating a host of cellular activities from transcription to protein turnover, placing a high demand on intracellular communication. Membrane contact sites (MCSs) formed between cellular organelles have emerged as key signaling hubs for coordinating an array of cellular activities. We have found that the endoplasmic reticulum (ER) MCS tethering protein PDZD8 is required for activity-dependent synaptogenesis. PDZD8 is sufficient to drive ectopic synaptic bouton formation through an autophagy-dependent mechanism and required for basal synapse formation when autophagy biogenesis is limited. PDZD8 functions at ER-late endosome/lysosome (LEL) MCSs to promote lysosome maturation and accelerate autophagic flux. Mutational analysis of PDZD8’s SMP domain further suggests a role for lipid transfer at ER-LEL MCSs. We propose that PDZD8-dependent lipid transfer from ER to LELs promotes lysosome maturation to increase autophagic flux during periods of high demand, including activity-dependent synapse formation.GRAPHICAL ABSTRACT

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EndophilinA-dependent coupling between activity-induced calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

Cited by 14 publications

References 118 publications

Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling

Identification of secretory autophagy as a novel mechanism modulating activity-induced synaptic remodeling

Endophilin-A/SH3GL2 calcium switch for synaptic autophagy induction is impaired by a Parkinson’s risk variant

PDZD8 promotes autophagy at ER-Lysosome contact sites to regulate synaptogenesis

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